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Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease

Citation:

Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019;22:401-412.

Abstract:

Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-beta (Abeta) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD(+) supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson's disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Abeta1-42 and Abeta1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Abeta plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.

Notes:

Fang, Evandro FHou, YujunPalikaras, KonstantinosAdriaanse, Bryan AKerr, Jesse SYang, BeimengLautrup, SofieHasan-Olive, Md MahdiCaponio, DomenicaDan, XiuliRocktaschel, PaulaCroteau, Deborah LAkbari, MansourGreig, Nigel HFladby, TormodNilsen, HildeCader, M ZameelMattson, Mark PTavernarakis, NektariosBohr, Vilhelm AengMC_PC_16034/MRC_/Medical Research Council/United KingdomZ01 AG000726-15/ImNIH/Intramural NIH HHS/Research Support, N.I.H., IntramuralResearch Support, Non-U.S. Gov'tNat Neurosci. 2019 Mar;22(3):401-412. doi: 10.1038/s41593-018-0332-9. Epub 2019 Feb 11.